Anders Koch, MD, PhD, MPH, Department of Infectious Diseases, Rigshospitalet University Hospital, Blegdamsvej 9, DK 2100 Copenhagen Ø, Denmark. E-mail: email@example.com
We present a recent case of Japanese encephalitis in a Danish male traveler to Cambodia, who we believe is the second Danish case within the last 15 years. Although both this and a number of other travel-related cases occurred in short-term travelers, change in vaccination recommendations is not recommended.
Japanese encephalitis (JE) affects more than 50,000 persons and causes 15,000 deaths per year, mostly in east and Southeast Asia.1 In endemic areas most cases occur among children. JE virus belongs to the flaviviridae family and is transmitted through a zoonotic cycle between culex mosquitoes, pigs, and water birds. Travelers to endemic areas are at risk of contracting JE and most western countries recommend vaccination in persons staying for longer periods (generally >4 wks) in rural, endemic areas. Yet, JE occurs very seldom among travelers from non-endemic countries.
We present a recent case of JE in a Danish male traveler to Cambodia, who we believe is the second Danish case within the last 15 years.
In July 2010, a previously healthy 61-year-old Danish man visited Cambodia for 14 days. He had stayed with his Danish family under private and good conditions primarily in the capital city Phnom Penh with a 3-day visit to Angkor Wat and the neighboring town of Siem Reap. The patient had not been vaccinated against JE nor used mosquito nets when sleeping due to air conditioning, but had used mosquito repellents. He recalled having been bitten by a few mosquitoes. As far as we know JE vaccination had not been advised to the patient.
Five days after returning to Denmark, the patient developed headache, dizziness, and fever of up to 40°C. The symptoms progressed over the next 2 days with development of paresis of the upper left extremity.
The patient was admitted to a local hospital. A lumbar puncture showed a white blood cell count of 145 cells/µL (83% polymorph nuclear), protein 0.49 g/L, a glucose level of 4.1 mmol/L, and no microorganisms by direct microscopy. Meningitis treatment with antibiotics and steroids was initiated. A cerebral computed tomography scan was normal.
On day 2 of admission, the patient was transferred to a specialized hospital. He became increasingly disorientated with development of lower left extremity paresis. On the suspicion of herpes encephalitis additional Acyclovir treatment was initiated.
On day 3 of admission, a magnetic resonance (MR) scan of the brain showed thalamic lesions (Figure 1), and on day 4 the patient was transferred to the intensive care unit and intubated. Five electroencephalograms within the following week were abnormal, but without paroxystic activity. On the fifth day of admission cerebrospinal fluid (CSF) culture from day 1 of admission remained negative, and antibacterial treatment for meningitis was discontinued (Figure 1).
The patient was extubated on the ninth day of admission with a GCS of 11. On the 14th day, an MR scan with angiosequences showed regression of the former abnormalities.
A large number of microbiological agents were suspected as possible causes of the patient's encephalitis, and blood and CSF samples were drawn repeatedly from days 1 to 36. By antibody and antigen tests at Rigshospitalet University Hospital, Department of Virology, Statens Serum Institut, Copenhagen, and Bernhard Nocht Institut, Hamburg, the patient was found negative for HSV, VZV, Enterovirus, Parechovirus, West Nile virus, Chicungunya virus, Rickettsia, Mycobacterium tuberculosis, tick borne encephalitis, Toxocara canis, malaria, and syphilis. Slightly elevated Dengue virus immunoglobulin M (IgM) antibodies with identical titers were found in blood samples on days 8 and 19, but were interpreted as unspecific reactions.
While blood and CSF samples drawn on day 1 of admission were negative for JE antibodies, blood samples drawn later were antibody positive: day 8 IgM 1 : 160 and immunoglobulin G (IgG) 1 : 1,280; day 19 IgM 1 : 320 and IgG 1 : 1,280; day 36 IgM negative and IgG 1 : 320. A CSF sample drawn on day 19 was antibody positive (IgM 1 : 10 and IgG 1 : 80). All samples were polymerase chain reaction negative for JE RNA (blood on days 8 and 19; CSF on days 1, 3, 8, 19, and 36).
The patient gradually improved over the next couple of months although he was continuously lethargic with mild cognitive impairment and upper left extremity paresis. Four months after symptom debut he suddenly had a generalized seizure. On arrival at hospital, he went into cardiac arrest and was declared dead. No autopsy was performed.
A classical presentation of symptomatic JE includes an incubation period of 5 to 15 days and 2 to 4 days of non-specific illness followed by headache, fever, rigor, gastrointestinal symptoms, and an encephalitis syndrome characterized by behavioral abnormality, alteration in sensorium, seizures, and neurological deficit in the form of hemiplegia, quadriplegia, or cerebellar signs.1 The upper extremities are more commonly affected than the lower limbs. Bilateral thalamic lesions in encephalitis patients are highly indicative of JE.2,3 About 50% of survivors have severe neurological sequels in the form of cognitive impairment, behavioral abnormality, focal weakness, seizures, and a variety of movement disorders.1 JE virus cannot usually be isolated in primarily infected patients who instead mount an IgM antibody response.
The patient's symptoms, clinical findings, course of disease, and JE antibody response indicative of acute infection were perfectly compatible with such a classical JE presentation.
The concerning thing about this case is that the patient was not at particular risk of JE. Although he had traveled to an endemic country (Cambodia), he had only been in Cambodia for 14 days, he had visited parts of Phnom Penh and Angkor Wat/Siem Reap, where pigs were not kept, and he had not had any contact with such animals. He had used mosquito repellent and had only to a lesser degree been bitten by mosquitoes. As far as we know this patient is the first JE patient among western travelers to Cambodia. Thus he did not belong to any risk group for whom vaccination would be recommended according to Danish and most other national guidelines.4
Up to 1992 all reported cases of JE among individual travelers to endemic countries occurred among long-term travelers.5 Subsequently, most western countries including Denmark recommend JE vaccinations in travelers to endemic countries staying >4 weeks in rural areas (with swine farming and wading birds), and for some countries only in parts of the year.4 However, in the most recent review of published JE cases among travelers from non-endemic countries 1973 to 2008 (n = 55), 13 of 37 (35%) had spent less than 4 weeks in JE endemic areas, although most had risk factors for infection.6 Also, in Thailand, where a peak in JE incidence is observed, 8 of 13 cases among travelers occurred outside of peak months.5 These facts, and as the newly introduced vaccine (Ixiaro®) is well tolerated, have led some authors to recommend considering changes in vaccination recommendations.5 Recently, the ACIP (Advisory Committee on Immunization Practices, CDC) suggested expanding vaccine recommendations to include also short-term travelers at risk.7 Others have recommended vaccinating all with a travel itinerary that includes rural areas.8
The present case was not, however, characterized by any particular risk behavior that would have resulted in vaccine recommendation according to any of these recent recommendations. A possible consequence of the case would be to recommend all short- and long-term travelers to JE endemic countries in the season to receive vaccination. JE is an extremely rare infection among travelers with estimated rates among US travelers to Thailand of 1/3.3 million and to Bali of 1/1.0 million.6 Approximately 180 million persons travel to Asia and the Pacific per year,9 hereof approximately 4.5 million tourists to Thailand alone.6 While any travel-related medical counselling must include the traveler's own perception and tolerance of risk, such a general recommendation to vaccinate millions of short-term travelers to JE endemic areas would be highly disproportionate to prevention of the extremely low number of clinical JE cases among travelers, given side effects and costs of vaccines.10
In conclusion, this case shows that JE may attack sporadically and underlines the importance of personal protective measures against mosquito bites that not only reduce the risk of JE, but also of other mosquito-borne infections.
We thank Drs Peter Skinhøj and Søren Thybo, Department of Infectious Diseases, Rigshospitalet University Hospital, for valuable comments to this article, and Dr Alex Nielsen, Department of Virology, Statens Serum Institut, Denmark, for help with interpretation of laboratory results. The Department of Diagnostic Radiology, Rigshospitalet University Hospital, is thanked for permission to print MR scans.
Declaration of Interests
The authors state that they have no conflicts of interest.